Dual chamber mixing device for a syringe

ABSTRACT

A mixing device and a retractable syringe comprising same are provided. The mixing device comprises concentric outer and inner barrels that form an outer chamber, the inner barrel having an inner chamber. A mixing plunger is slidably located in the outer chamber. A seal located in the outer chamber is capable of axial movement, in response to depression of the mixing plunger, from a first position in sealing engagement with one or more apertures in the inner barrel to a second position intermediate the apertures and vents in the outer barrel. This allows depression of the mixing plunger to force a first substance from the outer chamber through the apertures to mix with a second substance in the inner chamber. The mixed substance in the inner barrel is then delivered by the syringe with subsequent needle retraction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/566,079 filed Aug. 3, 2012, which claims priority to U.S. ProvisionalApplication No. 61/515,554 filed on Aug. 5, 2011, and U.S. ProvisionalApplication No. 61/545,653, filed on Oct. 11, 2011, each of which isincluded by reference herein in its entirety for all purposes.

FIELD

THIS INVENTION relates to mixing devices for syringes. Moreparticularly, this invention relates to a mixing device for aretractable syringe which enables storage, mixing, and injection of oneor more pharmaceutical substances.

BACKGROUND

It is known to provide syringes that comprise a mixing device for mixingdeliverable substances prior to injection. This allows, for example, adiluent to be added to a dehydrated, lyophilized, desiccated or powderedactive substance immediately prior to injection, which is particularlyuseful for substances that are subject to degradation or loss ofactivity when stored in a hydrated form.

The majority of mixing devices for syringes utilize sequential chambers,wherein the syringe has one barrel having a first proximal chamber and asecond distal chamber separated by, for example, a membrane orelastomeric seal. A number of such sequential-chamber mixing syringesutilize a bypass protrusion at a section of the barrel to enable fluidin the proximal chamber to bypass the dividing membrane and mix with thefluid or powder in the distal chamber.

However, some mixing syringes utilize concentric barrel configurations.The concentric barrel mixing syringes to date, however, require complexassemblies, multiple operation steps by the user, or other particularnuances that make them difficult to manufacture, assemble, or operate.For examples, some existing concentric barrel mixing syringes requireconcentric inner and outer barrels that are selectively rotatable withrespect to each other, and require one or more sealing rings whichcontain a passage means therein. The barrels must be rotated to align ahole in the inner barrel with the passage means in a sealing ring. Thepassage means in the sealing ring includes a radially extending openingthrough the sealing ring and a groove extending longitudinally of thesealing ring from the radially extending opening. This arrangement beingsuch that the groove connects the outer barrel with the radiallyextending opening and the radially extending opening selectivelyconnects the groove with the hole in the inner barrel. This enables flowof fluid from the outer barrel into the inner barrel to thereby mix thefluid with a substance in the inner barrel. Such configurations requirecomplex components and cumbersome requirements for the user to operatethe device.

Other concentric barrel designs utilize outer and inner telescopictubular elements seated inside a barrel and coaxial with thelongitudinal axis. The outer tubular element and barrel form a chamberwhich holds a reservoir of liquid. The outer tubular element has a fluidpassageway therein that allows the liquid to flow from the chamber intothe inner tubular element. The inner tubular element has an end nearbythe injection port with a seal thereon that has an orifice therein. Thisinner tubular element receives the end of the plunger with the resilientseal thereon. Accordingly, such mixing syringe configurations requirethree tubular elements, with the outer and inner concentric chambersresiding inside a third barrel.

There are numerous complexities associated with the use of concentricbarrels for mixing syringe configurations. In addition to thosedescribed above, mixing syringes utilizing concentric barrels must alsoaddress factors such as maintenance of container sterility, interactionof components for sealing, venting requirements, and distribution ofinternal forces, among others. Some dual chambered syringes haveconcentric inner and outer barrels that form an annular space to hold afluid and utilize one or more apertures between the inner and outerbarrels to enable flow of a liquid from the annular space into the innerbarrel and thereby mix the liquid with a substance in the inner barrel.The liquid is forced from the annular into the inner barrel bydepression of a plunger slidably movable in the annular space. First andsecond sealing bands are slidably received about the inner barrel in theannular space and are mutually spaced therealong. The position of thesealing bands can dictate how sterility of the fluid path is maintained,how internal forces are distributed, and how venting occurs. Forexample, both of the sealing bands may be initially positioned above theaperture to form a sealed annular volume for the first liquid component.Because of this arrangement, the aperture also must act as a vent toenable any air in the annular space distal to the second sealing band,which space must be sterilized, to be expelled via the aperture upondepression of the plunger. This venting requirement may causedifficulties and require additional equipment and processing steps, suchas requiring filling the inner chamber under vacuum to remove all airfrom the inner chamber and the distal portion of the outer barrel belowthe second reconstitution seal.

Generally, prior art mixing devices comprising concentric barrels arecomplicated in structure and often require rotation of the barrels toalign one or more apertures that enable a flow of a liquid substancefrom one chamber into another. Further to this, various sterility,sealing and venting arrangements have been used which have seriouslimitations in terms of ease of manufacture and operation of the mixingdevice.

SUMMARY

It is therefore an object of the invention to provide a mixing deviceand/or a syringe comprising the mixing device that alleviates one ormore of the problems associated with prior art mixing devices and/orsyringes, such as those referred to above.

In one aspect, the invention provides a mixing device for a syringe,said device comprising: an outer barrel and an inner barrel in asubstantially coaxial relationship, said mixing device capable ofcomprising a plurality of mixing substances wherein at least a firstmixing substance is locatable in an outer chamber between the outerbarrel and the inner barrel and at least a second mixing substance islocatable in an inner chamber in said inner barrel, the inner barrelcomprising one or more fluid paths through which the first mixingsubstance can enter the inner chamber in the inner barrel to therebyform a mixture with the second mixing substance; one or more vents influid communication with said outer chamber; and at least one seallocated in said outer chamber which is capable of axial movement from afirst position in sealing engagement with said one or more fluid pathsin the inner barrel to a second position at least partly between saidone or more fluid paths and said one or more vents. Suitably, the innerbarrel and the outer barrel are non-rotatable with respect to eachother.

The one or more fluid paths may comprise one or more apertures, holes,bores, ports, pass-throughs or conduits. These may be of any suitableshape, configuration, arrangement and/or number. Preferably, the fluidpath comprises a plurality of apertures. The apertures may be radialbores (i.e., normal to the axis of the barrel), angular bores (i.e., atan angle to axis of the barrel), helical (e.g., an angular and radialpath as it traverses the thickness of the barrel wall), or any number ofother configurations. The number and placement of the apertures, inlocational spacing and arrangement, may also be adjusted for the desiredmixing characteristics. As such, these parameters of the apertures maybe configured to promote the desired mixing, dilution, and other fluidflow characteristics of the mixing syringe.

Suitably, the mixing device further comprises a mixing plunger axiallymoveable within the outer chamber between the outer barrel and the innerbarrel to facilitate entry of the at least first mixing substance intothe inner chamber in the inner barrel and to facilitate axial movementof said seal from a first position in sealing engagement with said oneor more fluid paths in the inner barrel to said second positionintermediate or at least partly between said one or more fluid paths andsaid vent. The mixing plunger may have one or more extensions, such asfinger and/or thumb extensions, for ease of operation or aesthetics.

Preferably, the fluid mixing device includes a plurality of seals.Preferably, the plurality of seals comprises a proximal seal and adistal seal. In a preferred embodiment, the plurality of sealscomprises: a proximal seal engagably or connectably coupled, connectableor affixed to the mixing plunger and slidably moveable in the outerchamber; and said distal seal initially in a first position in sealingengagement with said one or more fluid paths in the inner barrel andslidably moveable in the outer chamber from sealing engagement with theone or more fluid paths to a second position intermediate or at leastpartly between said one or more fluid paths and said vent. The movementof the mixing plunger causes movement of the proximal seal to which theplunger is engaged or connectably coupled or affixed. This movement isrelayed to the first mixing substance in the outer chamber and,similarly, to the distal seal. Accordingly, axial movement of the mixingplunger indirectly (i.e., without needing direct contact) facilitatesaxial movement of the distal seal to said second position.

Preferably, the one or more vents are operable to facilitate exit of airfrom the outer chamber to atmosphere when the mixing plunger and distalseal are slidably moved in the outer chamber. The one or more vents maybe integrally formed in said outer barrel or may be a vent cap mountedor affixed to said inner and/or outer barrel. In either embodiment,conduits, holes, porous membranes, collapsible components and the likemay be utilized. For example, in at least one embodiment the vent cap isa plastic vent cap comprising one or more vent conduits, which plasticvent cap closes the outer chamber at the distal end of the outer barrelwhile permitting air to pass through the one or more vent conduits toatmosphere upon depression of the mixing plunger and movement of thedistal seal.

In one embodiment, the mixing device further comprises a removablesafety cap. Preferably, the removable safety cap prevents undesiredmovement of the distal seal prior to use (e.g., during transportation).The removable safety cap may comprise a plurality of protrusions whichare insertable through respective vent conduits so as to be adjacent to,or in contact with, the distal seal.

The mixing device may further comprise a barrel extension mounted to theouter barrel, or integrally formed with the outer barrel. The barrelextension may, optionally, include finger flanges or grips, or mayalternatively have optional finger flanges or grips connected thereto.

The mixing device may further comprise one or more mixing plunger locks.In one embodiment, elements of the mixing plunger and the barrelextension are engageable to form said mixing plunger lock. In oneparticular embodiment, the mixing plunger lock prevents removal of themixing plunger from the outer chamber during use. In another particularembodiment, the mixing plunger lock prevents proximal, axial movement ofthe mixing plunger after mixing is complete.

The first and second mixing substances may comprise one or more fluidsor one or more solids. The first mixing substance locatable in the outerchamber may be a fluid. The fluid may be a pharmaceutically active fluidor a pharmaceutically inactive fluid, such as a diluent. The secondmixing substance locatable in the inner chamber may be apharmaceutically active solid or a pharmaceutically active or inactivefluid.

In one embodiment, the inner chamber contains a pharmaceutically activesolid and the outer chamber contains a pharmaceutically inactivediluent, such as water, whereby entry of the diluent through the one ormore apertures from outer chamber into the inner chamber facilitatesmixing with the pharmaceutically active solid. The interaction betweenthe diluent and the pharmaceutically active solid enables reconstitutionof the pharmaceutically active solid for subsequent delivery to apatient.

In another embodiment, the inner chamber contains a pharmaceuticallyactive solid and the outer chamber contains a pharmaceutically activefluid, whereby entry of the fluid through the one or more apertures fromthe outer chamber into the inner chamber facilitates mixing with thepharmaceutically active solid in the inner chamber. The interactionbetween the pharmaceutically active fluid and the pharmaceuticallyactive solid enables reconstitution of the pharmaceutically active solidfor subsequent delivery to a patient.

In yet another embodiment, the inner chamber contains a firstpharmaceutically active fluid and the outer chamber contains a secondpharmaceutically active fluid, whereby entry of the firstpharmaceutically active fluid through the one or more from the outerchamber into the inner chamber facilitates mixing with the secondpharmaceutically active fluid in the inner chamber. The interactionbetween the first pharmaceutically active fluid and the secondpharmaceutically active fluid enables mixing of the pharmaceuticallyactive fluids for subsequent delivery to a patient.

Accordingly, the mixing device may facilitate the storage of multiplecomponent pharmaceutical substances in the outer and inner chambers,thereby maintaining the stability and efficacy of the pharmaceuticalsubstances during transport and over prolonged periods of storage.

In another aspect, the invention provides a syringe comprising adelivery plunger, a needle assembly, and a mixing device according tothe aforementioned aspect. The syringe may be utilized for storing,transporting, mixing, and injecting one or more mixing substances totreat a patient. As will be described further below, the syringe mayfurther contain safety features which retract the needle after use,providing desirable needle-stick prevention, and prevent re-use of thesyringe.

Suitably, the delivery plunger is slidably moveable within the innerbarrel of the mixing device to thereby facilitate delivery of the mixedsubstances or mixture to a user, patient or other recipient.

In a preferred form, the syringe is a retractable syringe that comprisesa retractable needle. Preferably, the delivery plunger is capable ofengaging the needle to retract the needle. Suitably, retraction of theneedle is facilitated by a biasing member such as a spring, elastic orother member capable of storing and releasing energy to facilitateneedle retraction. It will be appreciated that the retractable syringemay comprise any needle retraction mechanism that is operable with themixing device disclosed herein. By way of example, the needle retractionmechanism may be as described in International PublicationWO2006/119570, International Publication WO2006/108243, InternationalPublication WO2009/003234 and International Publication WO2011/075760,although without limitation thereto.

According to one embodiment, the retractable syringe comprises: aplunger comprising a biasing member, a plunger member, a plunger outerand one or more locking members, wherein the plunger member and plungerouter co-operate to releasably maintain said biasing member in aninitially energized state; and a needle assembly comprising theretractable needle, wherein the retractable needle comprises a cannulaand a needle body engageable by the plunger member.

Preferably, a plunger seal is mounted to the plunger member and iscapable of engaging said needle body.

Preferably, the needle assembly may further comprise a needle seal thatretains the retractable needle, wherein the cannula of the retractableneedle passes through the needle seal to permit delivery of the mixedsubstances or mixture to a user, patient, or other recipient.

In at least one embodiment, the mixing plunger further comprises arelease ring. Suitably, the release ring is at a proximal end of themixing plunger (i.e., opposite the distal end which engagably orconnectably coupled, connectable or affixed to the first or proximalseal) of the mixing plunger. The release ring may be a separatecomponent or integral with the mixing plunger. In a preferredembodiment, the release ring is a smaller diameter proximal portion ofthe mixing plunger. The release ring may activate needle retractionafter the plunger member of the retractable syringe has engaged theneedle body. Upon activation of needle retraction, the plunger memberand plunger outer disengage allowing the biasing member to expand fromits initially energized state. The plunger outer remains substantiallyin contact or connection with the release ring, while the plunger memberis axially translated in the proximal direction by release of thebiasing member to enable retraction of the cannula and needle body.

Suitably, the retractable syringe comprises one or more delivery plungerlocking systems. In one embodiment of said locking system, the plungerouter of the delivery plunger comprises a locking member which iscapable of engaging the release ring of the mixing plunger after needleretraction to thereby prevent or impede further movement of the deliveryplunger relative to the release ring. In another embodiment of saidlocking system, the plunger outer comprises a clip which engages theplunger member after retraction of the plunger member and the needleengaged therewith.

In at least one embodiment of the present invention, the retractablesyringe comprises a retraction mechanism essentially as described inWO2011/075760, with the functional modifications to the release ring ofthe mixing plunger described above.

In yet another aspect, the invention provides a method of assembling amixing device including the steps of:

-   (i) locating an outer barrel in coaxial alignment over an inner    barrel that has one or more apertures in communication with an inner    chamber of the inner barrel, the coaxial alignment of the outer and    inner barrels forming an outer chamber, wherein the outer chamber    has one or more vents in fluid communication therewith which are    located distally of the one or more apertures; and-   (ii) inserting a seal into the outer chamber in releasable sealing    engagement with the one or more apertures.

In one embodiment, the method further includes, prior to step (i),affixing a vent cap comprising the one or more vents to a portion of theinner barrel that is located distally of the one or more apertures.Preferably, the distal end of the outer barrel is connected to the ventcap.

Preferably, the method further includes the step of inserting a needleassembly into the inner chamber located distally of the one or moreapertures.

In a further aspect, the invention provides a method of manufacturing asyringe comprising a mixing device, the method including the steps of:

-   (i) locating a first mixing substance in an outer chamber of the    mixing device and inserting a first or proximal seal in the outer    chamber of the mixing device in contact with the first mixing    substance;-   (ii) locating a second mixing substance in an inner chamber of the    mixing device;-   (iii) inserting a delivery plunger into the inner barrel, wherein    the delivery plunger is proximal to one or more apertures of the    inner barrel; and-   (iv) mounting a mixing plunger in the outer chamber, wherein the    mixing plunger contacts the first or proximal seal.

In a still further aspect, the invention provides a method of operatinga syringe comprising a mixing device, said method including the stepsof:

-   (i) operating a mixing plunger of the mixing device to thereby mix a    plurality of substances;-   (ii) operating a delivery plunger to deliver the substances mixed at    step (i) to a recipient.

In at least one embodiment, the method of operating a syringe comprisinga mixing device further includes: (iii) activating a needle retractionmechanism to retract the needle into the syringe. Preferably, theactivation of the needle retraction mechanism occurs after substantiallyall of the substances are delivered to the recipient.

Throughout this specification, unless otherwise indicated, “comprise”,“comprises” and “comprising” are used inclusively rather thanexclusively, so that a stated integer or group of integers may includeone or more other non-stated integers or groups of integers.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the invention are described herein withreference to the following drawings wherein:

FIG. 1A shows a side view of an embodiment of a mixing device;

FIG. 1B shows a side view of an embodiment of a mixing device withdistal seal removed to show fluid path apertures;

FIG. 2 shows an embodiment of a mixing device further comprising anoptional safety cap mounted thereto;

FIG. 3A shows an embodiment of a retractable syringe comprising a mixingdevice;

FIG. 3B shows an exploded view of an embodiment of a retractable syringecomprising a mixing device;

FIG. 4 shows a sectional view of a delivery plunger of a retractablesyringe;

FIG. 5 shows an embodiment of a retractable syringe comprising a mixingdevice after removal of the safety cap prior to depression of a mixingplunger of the mixing device;

FIG. 6 shows an embodiment of a retractable syringe comprising a mixingdevice after depression of the mixing plunger of the mixing device;

FIG. 7 shows an embodiment of a retractable syringe comprising a mixingdevice after depression of the delivery plunger;

FIG. 8 shows an embodiment of a needle assembly engaged by a deliveryplunger prior to retraction;

FIG. 9 shows an embodiment of a release ring disengaging a plunger outerfrom a plunger inner to facilitate spring decompression and needleretraction; and

FIG. 10 shows an embodiment of locking systems of a retractable syringe.

DETAILED DESCRIPTION

Referring to FIG. 1A and FIG. 1B an embodiment of mixing device 100comprises inner barrel 110 comprising wall 111 and inner chamber 112,outer barrel 120 comprising wall 121 and mixing plunger 130. Outerchamber 140 is formed between wall 111 of inner barrel 110 and wall 121of outer barrel 120. Inner barrel 110 and outer barrel 120 may be madeof any of a number of materials including plastics and glass, but arepreferably made of glass. Inner barrel 110 and outer barrel 120 are in asubstantially concentric relationship, such that inner barrel 110 andouter barrel 120 possess a substantially common, central longitudinalaxis. Inner barrel 110 and outer barrel 120 are non-rotatable withrespect to each other.

Outer barrel extension 150 comprises finger grips 151A, B to assistgripping by a user. Outer barrel extension 150 may be integrally formedin outer barrel 120 or may be a separate component affixed to outerbarrel 120. Outer barrel extension 150 further comprises inner lip 152and locking ring 153, the functions of which will be described in moredetail hereinafter.

Typically, outer chamber 140 contains a liquid substance and innerchamber 112 contains a solid substance, whereby the liquid substance ismixable with the solid substance in the inner chamber 112 to form amixed substance suitable for injection. In at least one embodiment,however, the outer chamber 140 and inner chamber 112 both contact liquidsubstances.

In the embodiment shown in FIGS. 1A and 1B, outer barrel 120 is shorterthan inner barrel 110. This configuration provides certain benefits suchas, for example, allowing a heat transfer sleeve (not shown) to beplaced around and in direct contact with a portion of inner barrel 110.This is useful to enable in situ lyophilization of a liquid substancelocated in inner chamber 112, by permitting filling with a liquidsubstance and then lyophilizing the liquid substance into a powderduring or after manufacture of mixing device 100.

In other embodiments, inner barrel 110 and outer barrel 120 are ofsubstantially similar length. This embodiment may be more aestheticallypleasing or provide additional volume by way of outer chamber 140. Alsolocated in outer chamber 140 are first or proximal seal 160 and secondor distal seal 170 slidably located therein. Outer barrel 120 furthercomprises vent cap 123 comprising plurality of vents 122, whereby ventedspace 142 is located between vents 122 and second or distal seal 170.Because the substances do not contact this vented space 142, ventedspace 142 may be unsterile and open to the atmosphere. This featureenables displacement of second or distal seal 170 towards plurality ofvents 122 during the mixing step of operation, thereby opening one ormore apertures 114 for passage of fluid from the outer chamber to theinner chamber. The fluid path from outer chamber 140 to inner chamber112 remains sterile as a result of the displaced location of second ordistal seal 170.

Mixing plunger 130 comprises button 131 and cylindrical shaft 132 whichis slidably, axially moveable within outer chamber 140. Mixing plunger130 may further comprise spring prongs 133A, B located on shaft 132biased outwardly from shaft 132. Spring prongs 133A, B are movedinwardly (i.e., against bias) when inserting mixing plunger 130 intoouter chamber 140 of mixing device 100. In the assembled mixing device100, spring prongs 133A, B prevent removal of mixing plunger 130 fromouter chamber 140, as will be described in more detail hereinafter.Mixing plunger 130 further comprises locking prongs 134A, B (134B notvisible) located on shaft 132 biased outwardly from shaft 132. Lockingprongs 134A, B are biased outwardly to engage inner lip 152 of barrelextension 150 to facilitate locking mixing plunger 130 from proximalmovement after mixing is complete.

Mixing plunger 130 further comprises release ring 136 at a proximal end(i.e., proximal to a user) of cylindrical shaft 132. Release ring 136may be a separate component or an integral component of mixing plunger130. In a preferred embodiment, release ring 136 is a smaller diameterproximal portion of mixing plunger 130. The functions of release ring136 will be described in more detail hereinafter.

First or proximal seal 160 is in contact with the distal end 135 ofcylindrical shaft 132 of mixing plunger 130. Second or distal seal 170is positioned distally from proximal seal 160 within outer chamber 140.First or proximal seal 160 is axially, slidably moveable within outerchamber 140 by contact with and movement of the shaft 132 of mixingplunger 130. As best seen in FIG. 1B, apertures 114 on inner barrel wall111 provide a fluid path that allows fluid from outer chamber 140 toflow into inner chamber 112. Initially, second or distal seal 170 is insealing engagement with apertures 114 (e.g., covering apertures 114;compare FIG. 1A and FIG. 1B).

In the embodiment shown in FIG. 2, optional safety cap 180 is removablymounted to bracket 125 of outer barrel 120. Safety cap 180 comprisesring body 182 and protrusions 181 which are inserted through respectivevents 122 (not visible in FIG. 2) so as to be adjacent to, or in contactwith, distal seal 170. This prevents undesired movement of distal seal170, such as in response to air pressure changes during transportationor by inadvertent movement of mixing plunger 130 prior to intendedactivation by the user.

Referring now to FIGS. 3-4 and FIGS. 8-10, mixing device is a componentof retractable syringe 1000 that comprises delivery plunger 200 andretractable needle assembly 400. Delivery plunger 200 is axially,slidably movable in inner chamber 112 of inner barrel 110 of mixingdevice 100 to thereby deliver the fluid contents of the inner chamber110 and subsequently retract retractable needle 400.

Plunger 200 comprises plunger member 210 comprising shaft 211, annularledge 212 and seal-engaging member 216, which in this embodiment isscrew threaded projection 217, which engages complementary,screw-threaded recess 820 of plunger seal 800. Plunger seal 800 furthercomprises needle-engaging portion 810.

Plunger 200 further comprises plunger outer 220 having elongate body 221with base 225 and head 222 and locking member 227.

Releasably connected with plunger member 210 is control rod 230comprising button 231, arm 232 and shaft 233. Plunger 200 furthercomprises compressed spring 270 which is mounted between plunger member210 and plunger outer 220, held in an initially compressed state betweenledge 212 of plunger member 210 and base 225 of plunger outer 220. In atleast one embodiment, control rod 230 is releasably coupled to plungermember 210 by way of shaft 233 which is releasably connected to plungermember 210 by optional frangible junction 234 (shown in FIG. 10).Control rod 230 also releasably engages plunger outer 220 to therebyretain spring 270 in an initially compressed state held between annularledge 212 of plunger member 210 and base 225 of plunger outer 220 inelongate portion 221. Initially, ledge 235 of arm 232 abuts rim 229 ofplunger outer 220 to thereby retain control rod 230 and prevent axialmovement of control rod 230 relative to plunger outer 220. However, arm232 of control rod 230 is resiliently flexible and movable in thedirection of the solid arrow shown in FIG. 4, which will allowdisengagement of control rod 230 from plunger outer 220 to facilitatedecompression of spring 270, as will be described hereinafter.

Needle assembly 400 comprises retractable needle 400 comprising cannula410 and needle body 420, retainer 300, needle seal 430 and ejector 600.

Operation of mixing device 100 will be described with particularreference to FIGS. 1A, 1B, 5 and 6. In these embodiments, outer chamber140 contains a fluid substance and inner chamber 112 contains a solidsubstance, whereby the fluid is mixable with the solid substance in theinner chamber 112 to form a mixed, fluid substance suitable forinjection. As evident in FIG. 5, safety cap 180 (shown in FIG. 2) hasbeen removed from outer barrel 120 to allow movement of second or distalseal in outer chamber 140.

Initially, second or distal seal 170 covers apertures 114 in innerbarrel wall 111 to prevent movement of liquid from outer chamber 140into inner chamber 112. Depression of mixing plunger 130 (i.e., axialmovement towards needle 400 in the direction of the hatched arrow) inthe direction of the solid arrow forces first or proximal seal 160distally in outer chamber 140 which forces liquid contained in outerchamber 140 to displace second or distal seal 170 (i.e., towardsretractable needle 400), thereby opening apertures 114 to permit fluidto transfer from outer chamber 140 to inner chamber 112.

As shown in FIG. 6, continued depression of mixing plunger 130 in thedirection of the hatched arrow forces further distal movement of firstor proximal seal 160 within outer chamber 140, forcing continued fluidflow from outer chamber 140 to inner chamber 112, until first orproximal seal 160 is in contact with second or distal seal 170. Seals160 and 170 may be caused to reach end of travel within outer chamber140, where second or distal seal 170 will contact with vent cap 123. Inthis position, either seal 160 is in sealing engagement (i.e., covering)with apertures 114 or both seals 160 and 170 may be in partial sealingengagement with apertures 114. The latter is possible, for example, whenfluid flow from outer chamber 140 to inner chamber 112 does not requirethe second or distal seal 170 to fully uncover the apertures 114.

At this point, fluid delivery from outer chamber 140 to inner chamber112 is complete. Mixing plunger 130 cannot be withdrawn from outerchamber 140, as locking prongs 134A, B on mixing plunger shaft 132(which are outwardly biased) would engage inner lip 152 of barrelextension 150 to form a lock that prevents proximal movement (i.e.,towards a user) of mixing plunger 130 beyond this point. Locking mixingplunger 130 after mixing may be useful in directing the force ofdelivery plunger 200 through needle 400 to inject the liquid substance,instead of forcing the liquid substance back into outer chamber 140.This may also be achieved by the final positioning of first or proximalseal 160 in sealing engagement with apertures 114. Similarly, full axialmovement of mixing plunger 130 and/or engagement between mixing plunger130 and one or more detent aspects of outer barrel 120 may unlockdelivery plunger 200 or a locking aspect of inner barrel 110 to enableaxial depression of delivery plunger. This provides useful user feedbackto ensure that the proper injection procedures are followed with thedevice and that reconstitution or mixing of the drug treatment(s) isenabled prior to injection into the patient.

It will be appreciated that venting space 142 between the second ordistal seal 170 and vents 122 is never in contact with any substance(s)in mixing device 100, hence there is no need to maintain sterility inthe area of the venting space 142. Venting space 142 may fill with air,which is displaced out of the annular space between outer barrel 120 andinner barrel 110 and between vents 122 and the second or distal sealupon depression of mixing plunger 130 and axial movement of second ordistal seal 170. Furthermore, because second or distal seal 170initially covers apertures 114 in wall 111 of inner barrel 110,sterility of this fluid path between outer chamber 140 and inner chamber112 is maintained during use of mixing device 100. Only second or distalseal 170 is potentially in contact with any non-sterile portion of outerbarrel 120 and inner barrel 110, as fluid is caused to flow from outerchamber 140 into inner chamber 112 without ever contacting thenon-sterile portion.

It will also be appreciated that retractable syringe 1000 is a “closedsystem,” meaning there is no venting of the fluid path other than byneedle injection. Accordingly, delivery plunger 200 may axially move ininner chamber 110 in the proximal direction (i.e., towards a user) inresponse to the distal movement of mixing plunger 130. This is becausedistal movement of mixing plunger 150 forces liquid from outer chamber140 into the inner chamber 112 and increases the pressure and/or fluidvolume within inner chamber 112. With rigid needle sheath 119 stillclosed over retractable needle 400, there is no space for volumeexpansion other than to force delivery plunger 200 in the proximaldirection within inner barrel 120. This is a desirable response as itprovides visual and tactile indication to the user that the mixing hascompleted and that the injection may be initiated.

Upon completion of mixing of substances in inner chamber 112, syringe1000 is ready to use. Rigid needle shield 119 is removed, cannula 410 ofneedle 400 is inserted into a recipient and delivery plunger 200 isdepressed to deliver the mixed, fluid contents of inner chamber 112 tothe recipient. Standard medical practices, such as manual agitation ofthe syringe to further facilitate mixing of the substances and/orpriming the syringe to remove any residual air prior to injection, maybe performed prior to needle insertion and injection of fluid contents.

In at least one embodiment of the present invention, the needleretraction is essentially similar to that described in WO2011/075760,and will be briefly described as follows with reference to FIGS. 7-9.During delivery of fluid contents, delivery plunger 200 moves axiallythrough barrel 110 in the direction of the solid arrow in FIG. 7. Asshown in FIG. 8, plunger seal 800 bears against needle seal 430, whichin turn bears against ejector 600. Further to this, ejector ring 610moves hook-ends 321A, B of arms 320A, B of retainer 300 radiallyoutwardly in the direction of the solid arrows in FIG. 8, therebydisengaging needle body 420 from retainer 300 to release retractableneedle 400 for subsequent retraction. At this point, recessed seat 810of plunger seal 800 has engaged segment 425 of retractable needle body420 and recess 860 has received fluid end 412 of cannula 410. Thiseffectively couples retractable needle 400 to plunger member 210.

As shown in FIG. 9, in order for retractable needle 400 to retract atthe end of delivery of fluid contents, compressed spring 270 mustdecompress, which is facilitated by plunger member 210 disengaging fromplunger outer 220. This disengagement is facilitated by release ring136. As plunger member 210 and plunger outer 220 are substantially fullydepressed (i.e., axially translated in the distal direction as per thehatched arrow) to inject fluid from inner chamber 110, one or both maycontact release ring 136. Through this contact, release ring 136 movesarm 232 radially inwardly (in the direction of the solid arrow) and outof engagement with rim 229 of plunger outer 220. This disengagementallows compressed spring 270 to decompress and push against ledge 212 ofplunger member 210 to thereby retract plunger member 210 with controlrod 230 coupled thereto. Plunger outer 220 remains substantially incontact or connection with release ring 136, while plunger member 210coupled to needle body 420 and cannula 410 is axially translated in theproximal direction by decompression of spring 270, thereby retractingcannula 410 and needle body 420.

Suitably, retractable syringe 1000 comprises one or more locking systemsfor delivery plunger 200. As shown in FIG. 10, in one embodiment of saidlocking system, plunger outer 220 of delivery plunger 200 compriseslocking member 227 which comprises edge 228 engaging underside 137 ofrelease ring 136 after needle retraction to thereby prevent or impedefurther movement of delivery plunger 200 relative to the release ring,as shown in FIG. 10. Accordingly, in addition to initially assisting inthe activation of needle retraction, the release ring 136 maysecondarily function to lock delivery plunger 200 after initial use tothereby prevent re-use.

Another of said one or more locking systems for plunger 200 is alsoshown in FIG. 10. After retraction, clip 224 of plunger outer 220 andlocking groove 219 of plunger member 210 co-operate to form a lockingsystem that locks plunger member 210 and plunger outer 220 together andprevent movement of plunger member 210 relative to plunger outer 220.

At the end of refraction of plunger member 210 and retractable needle410, control rod 230 can optionally be broken from plunger member 210 atoptional frangible junction 234 and manually removed from retractablesyringe 100 and discarded as “clean” waste so that there is little ifany plunger member 210 protruding externally from the syringe with whichto attempt to force delivery plunger 200 back into barrel 110 andattempt to re-engage the needle (not shown). This optional frangiblejunction 234 (shown in FIG. 10) may be located along plunger member 210at a point that would extend in the proximal direction beyond head 222when the syringe is in the retracted position and, optionally, lockedfrom re-use.

Certain other variations of mixing device 100 are contemplated. As analternative to rigid needle sheath 119, a venting rigid needle shieldmay include a first protective component and a second protectivecomponent, the first and second components being slidably engaged suchthat venting may occur when the components are slid apart to an expandedstate. When the first and second components are in an engaged andcontracted state, no venting is permitted through the needle end.However, when the first and second components are in an engaged butexpanded state (e.g., slid apart along an axis), air is permitted tovent through the needle without risk of exposing the needle to thepatient. Such venting through the needle may be used, if needed, to ventthe change in air volume and/or pressure within inner chamber 112 upondisplacement of fluid from outer chamber 140 into inner chamber 112.

In another variation, at the end of depression mixing plunger 130 may belocked to outer barrel 120 by way of complementary detent aspects (notshown) which engage at a point of axial travel in the distal directionby mixing plunger 130 to prevent subsequent axial travel in the proximaldirection. These complementary detents may be used together with, or asan alternative to, locking prongs 134A, 134B described previously.

In yet another variation, barrel extension 150 may include theaforementioned complementary detent aspects (not shown) of outer barrel120 which engage mixing plunger 130 upon full axial translation ofmixing plunger in the distal direction.

In yet another variation, inner chamber 140 may be compartmentalized(i.e., comprising a plurality of compartments) such as by one morefrangible or porous membranes, walls, sealing members or the like, witheach compartment containing a different fluid or solid substance,whereby depression of mixing plunger 130 facilitates mixing of eachdifferent fluid or solid substance. Additionally, or alternatively,inner chamber 112 may be similarly compartmentalized, each compartmentcomprising a different fluid or solid substance. Accordingly, mixingdevice 100 may include two or more substances for mixing and injection.

It will be appreciated from the foregoing that the mixing device andsyringe disclosed herein provide an efficient and easily-operated systemfor mixing multiple substances prior to delivery by the syringe. Thereis no need to rotate or otherwise orient the inner and outer barrelsprior to use to open or align fluid pathways, unlike in many prior artmixing devices such as those previously described. The positioning ofthe distal seal relative to the vents in the outer barrel and theapertures in the inner barrel keeps the contents of the mixing devicesterile while providing adequate venting, which is in contrast to manyprior art mixing devices such as previously described.

Assembly and/or manufacturing of mixing device 100, retractable syringe1000, or any of the individual components may utilize a number of knownmaterials and methodologies in the art. For example, a number of knowncleaning fluids such as isopropyl alcohol and hexane may be used toclean the components and/or the devices. A number of known adhesives orglues may similarly be employed in the manufacturing process.Additionally, known siliconization fluids and processes may be employedduring the manufacture of the novel components and devices. To add theone or more apertures to the inner barrel, known drilling or boringmethodologies such as mechanical or laser drilling may be employed.Furthermore, known sterilization processes may be employed at one ormore of the manufacturing or assembly stages to ensure the sterility ofthe final product.

In one embodiment, a method of assembling the mixing device includes thesteps of:

-   (i) affixing a vent cap having one or more vents to a distal end of    an inner barrel, wherein the inner barrel has one or more apertures    passing therethrough and the vent cap is affixed distally of the one    or more apertures;-   (ii) placing an outer barrel in coaxial alignment over an inner    barrel and connecting the distal end of the outer barrel to the vent    cap, wherein the outer barrel has a diameter greater than the    diameter of the inner barrel and the barrels are aligned such that    the annular space between the barrels forms an outer chamber;-   (iii) inserting a distal seal into the outer chamber and positioning    the distal seal in sealing engagement with the one or more    apertures; and-   (iv) inserting a needle assembly into the inner chamber, such that    the needle assembly resides distally of the apertures.

As discussed above, a glue or adhesive may be utilized to affix one ormore components of the mixing device to each other. Alternatively, oneor more components of the mixing device may be a unified component. Forexample, the venting cap may be a separate component affixed by a glueto the inner and outer barrels, or the venting cap may be a preformedaspect at the distal end of the outer barrel which is glued to the innerbarrel. These components may be sterilized individually or together, andmay be assembled in a sterile environment or sterilized after assembly.One or more of the barrels may be siliconized prior to or afterassembly.

The mixing device may be utilized as a component of a mixing syringe. Inone embodiment, the method of manufacturing a syringe comprising amixing device includes the steps of:

-   (i) at least partly filling a first fluid substance in the outer    chamber and inserting a proximal seal into the outer chamber in    contact with the first fluid substance;-   (ii) at least partly filling a second fluid substance in the inner    chamber and inserting a delivery plunger into the inner barrel,    wherein the delivery plunger is proximal to the apertures of the    inner barrel; and-   (iii) mounting a mixing plunger in the outer chamber, wherein the    mixing plunger may rest in contact with the proximal seal.

A number of known filling processes and equipment may be utilized toachieve the filling steps of the syringe manufacturing process. In oneembodiment, the second fluid substance may be filled as a liquidsubstance and lyophilized in situ using certain barrel heat transferequipment. The needle assembly, delivery plunger, and other componentsdescribed in these manufacturing and assembly processes may be asdescribed above or may be a number of similar components which achievethe same functionality as these components.

Throughout the specification, the aim has been to describe the preferredembodiments of the invention without limiting the invention to any oneembodiment or specific collection of features. Various changes andmodifications may be made to the embodiments described and illustratedwithout departing from the present invention.

The disclosure of each patent and scientific document, computer programand algorithm referred to in this specification is incorporated byreference in its entirety.

What is claimed is:
 1. A mixing device for a syringe, said mixing devicecomprising: an inner barrel including an inner chamber, an outer barreldisposed about at least a portion of the inner barrel, the outer barrelincluding an outer chamber at least partially formed between the innerbarrel and the outer barrel, a distal seal disposed within the outerchamber, the distal seal separating the outer chamber into a firstmixing substance space disposed proximally to the distal seal and avented space disposed distally to the distal seal, the outer barrelincluding at least one vent extending through the outer barrel tofluidly connect the vented space with an exterior of the mixing device,the at least one vent being disposed distally to the distal seal, atleast one aperture extending through the inner barrel and opening intothe inner and outer chambers, the distal seal being slidably disposedwithin the outer chamber for movement in a distal direction between afirst and a second position, the second position being distal to thefirst position, wherein movement of the distal seal from the firstposition to the second position expels air from the vented space in theouter barrel through the at least one vent as a volume of the ventedspace is reduced.
 2. The mixing device of claim 1 wherein movement ofthe distal seal from the first position to the second position resultsin a reduction in the volume of the vented space.
 3. The mixing deviceof claim 1 wherein the distal seal covers the at least one aperture whenthe distal seal is disposed in the first position, and the distal sealat least partially uncovers the at least one aperture to fluidly connectthe inner chamber and the first mixing substance space when the distalseal is in the second position.
 4. The mixing device of claim 1 furtherincluding a proximal seal disposed within the outer chamber proximallyto the distal seal, the proximal seal being adapted for sliding movementin the distal direction within the outer chamber, the proximal anddistal seals along with the inner and outer barrels defining the firstmixing substance space, the distal seal and the outer and inner barrelsdefining the vented space distal to the distal seal.
 5. The mixingdevice of claim 4 wherein movement of the proximal seal in the distaldirection results in movement of the distal seal from the first positionto the second position and the expulsion of air from the vented space tothe exterior of the mixing device.
 6. The mixing device of claim 1further including a mixing plunger axially movable within the outerbarrel, movement of the mixing plunger in the distal direction resultingin movement of the distal seal in the distal direction.
 7. The mixingdevice of claim 6 wherein the mixing plunger includes a proximal sealdisposed within the outer chamber proximally to the distal seal, theproximal seal being adapted for sliding movement in the distal directionwithin the outer chamber, the proximal and distal seals along with theinner and outer barrels defining the first mixing substance space, thedistal seal and the outer and inner barrels defining the vented spacedistal to the distal seal, depression of the mixing plunger moving theproximal seal in the distal direction, movement of the proximal seal inthe distal direction resulting in movement of the distal seal in thedistal direction.
 8. The syringe comprising a delivery plunger, a needleand the mixing device according to claim 7, the delivery plunger beingaxially, slidably movable in the inner chamber.
 9. The syringe of claim8 further including a biasing member capable of storing and releasingenergy to facilitate retraction of the needle into the syringe.
 10. Thesyringe of claim 9, wherein the delivery plunger includes the biasingmember, a plunger member, a plunger outer and one or more lockingmembers; wherein the biasing member is a spring; wherein the plungermember and plunger outer cooperate to releasably maintain said biasingmember in an initially energized state; the syringe further comprising aneedle assembly comprising the retractable needle, wherein theretractable needle comprises a cannula and a needle body engageable bythe plunger member.
 11. The mixing device of claim 6, further comprisinga mixing plunger lock which prevents removal of the mixing plunger fromthe outer chamber of the mixing device.
 12. The mixing device of claim 1wherein the outer barrel includes a vent cap disposed at a distal end ofthe outer chamber, the at least one vent extending through the vent cap.13. The mixing device of claim 12 wherein the outer barrel furtherincludes a cylindrical wall, the vent cap being disposed at a distal endof the cylindrical wall.
 14. The mixing device of claim 1 furtherincluding a removable safety cap having at least one protrusioncorresponding to the at least one vent, the at least one protrusionbeing disposed within a respective at least one vent and adjacent to orin contact with a distal surface of the distal seal to inhibit axialmovement of the distal seal, the at least one protrusion being removablefrom the at least one vent to fluidly connect the vented space with aexterior of the outer barrel.